MicroRNAs (miRNAs) are a highly abundant class of endogenous non-coding RNAs (18-25 nucleotides in length), which contributes to cancer initiation and progression, and are differentially expressed in normal tissues and cancers. They regulate gene expression by silencing the expression of their target genes post-transcriptionally, causing either mRNA molecule degradation or translational inhibition. Many miRNAs have been implicated in human cancers, including breast cancer. miRNA profiling studies have led to the identification of miRNAs that are aberrantly expressed in human breast cancer. They can function as either tumor suppressors or oncogenes. Thus, tumor formation, progression and metastasis may arise from a suppression or deletion of tumor suppressor miRNAs and/ or overexpression or amplification of an oncogenic miRNA. Since early detection of the preneoplastic lesion remains the key to improving patient outcomes and survival, reducing patient suffering and costs, new biomarkers to differentiate between benign and precancerous lesions, and between histological similar precancerous lesions with potentially different outcomes, would aid in effective intervention, prevention and treatment. Intraductal epithelial proliferations of the breast are classified into three groups histologically and clinically. They are ductal epithelial hyperplasia (DEH), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). A woman with DEH has a slightly higher chance of developing breast cancer while ADH is a precancerous lesion that increases the risk by 4-5 folds. While DEH is morphologically and phenotypically heterogeneous, ADH and DCIS are homogeneous in cell type and marker expression. To better understand the progression of ductal breast cancer development and distinguish between the normal epithelium, DEH, ADH and DCIS stages, we propose to identify miRNA biomarkers from Formalin-Fixed, Paraffin-Embedded (FFPE) breast tissues and decipher the role of miRNAs in breast tumorigenesis. This project will not only enhance discoveries and knowledge of miRNA deregulation in early stage cancer progression but also enable us to develop novel approaches for prevention, diagnosis, prognosis, and treatment, such as blood-based miRNA assays. The success of this project would have a broad impact in research of other diseases, health disparities and policy making due to the world-wide availability of FFPE samples with rich clinical data. PUBLIC HEALTH RELEVANCE: Many miRNAs have been implicated in several cancers, including breast cancer. miRNA profiling studies have led to the identification of miRNAs that are aberrantly expressed in human breast cancer. The goal of this project is to enhance discoveries and knowledge of miRNA deregulation in early breast cancer progression and to develop novel approaches for prevention, diagnosis, prognosis, and treatment, such as blood-based miRNA assays.